Therapeutic efficacy of cenegermin in the management of neurotrophic keratitis: a systematic review and meta-analysis of randomized controlled trials.

Abstract

Background: Neurotrophic keratitis (NK) is a rare, degenerative disease of the cornea that arises from impaired trigeminal nerve innervation. The condition leads to progressive corneal anesthesia, epithelial breakdown, ulceration, and potential perforation. Cenegermin, a recombinant form of human nerve growth factor, is the first pharmacotherapy approved for this indication and operates through a disease-modifying mechanism that promotes corneal nerve regeneration.

Objectives: To evaluate the therapeutic efficacy and safety profile of topical cenegermin (20 mcg/mL) compared with vehicle in adults with moderate to severe NK (Mackie classification stage 2 or 3) by quantitatively synthesizing evidence from randomized controlled trials (RCTs).

Design: Systematic review and meta-analysis of RCTs, conducted in accordance with the PRISMA 2020 statement and the Cochrane Handbook for Systematic Reviews of Interventions.

Data sources and methods: PubMed, Web of Science, and Cochrane CENTRAL were searched from inception through February 2026. Two double-masked, vehicle-controlled RCTs (the REPARO trial and the NGF0214 trial) enrolling 148 adults were included. Data were pooled using random-effects models (DerSimonian-Laird) and reported as risk ratios (RRs) with 95% confidence intervals (CI). Risk differences (RDs) and the number needed to treat (NNT) were also computed. Certainty of evidence was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

Results: Cenegermin substantially increased the probability of complete corneal healing at 8 weeks, with a pooled RR of 1.84 (95% CI 1.34-2.52; z = 3.8; p = 0.0001) and minimal between-study heterogeneity (I-squared = 0%; tau-squared = 0.00). The model-based pooled RD was 0.42 (95% CI 0.24-0.60), yielding an NNT of 3 (95% CI 2-5). The crude pooled event rates were 72.6% in the cenegermin group versus 38.7% in the vehicle group. Regarding safety, the pooled RR for any adverse event was 1.07 (95% CI 0.64-1.78; p = 0.80), showing no significant difference between groups. The overall certainty of evidence was rated as moderate for both outcomes under the GRADE framework.

Conclusion: Cenegermin is an effective and well-tolerated, disease-modifying therapy for moderate to severe NK. It nearly doubles the likelihood of complete corneal healing and represents an important addition to the therapeutic options available for this debilitating condition. Larger, independently funded trials with longer follow-up are warranted to confirm these findings and to establish its position within the treatment algorithm.

Trial registration: PROSPERO CRD420251103148.